Although estrogens are believed to play a key role in the development of endometrial cancer, evidence indicates that other regulatory molecules are also involved in the disease. High-energy diets, physical inactivity, obesity, insulin resistance, and diabetes are found to be associated with the risk of endometrial cancer, and these associations cannot be explained entirely by the role of estrogens. Mitogenic growth factors are suspected to be involved in these relationships, given their possible link to these lifestyle factors, and their ability to stimulate cell proliferation, to inhibit apoptosis, and to interact synergistically with sex steroid hormones in regulating important cellular activities in sex organs. To date, there have been few epidemiologic studies addressing the role of mitogenic growth factors in endometrial cancer, especially their interplay with lifestyle factors. In this proposal, we hypothesize that certain genetic polymorphisms in the genes encoding mitogenic growth factors and molecules involved in their signal transduction pathway are associated with strong mitogenic activities; these activities synergistically interact with a lifestyle of high-energy diets and low physical activity, resulting in elevated risk for endometrial cancer. To test this hypothesis, we will carry out a population-based case-control study in the state of Connecticut. We will enroll 900 incident cases with primary endometrial cancer, aged 35-79 years, and 900 age-matched control women. Controls will be selected randomly from the state through random-digit dialing. Detailed personal information including menstrual and reproductive history, medical history, estrogen usage, dietary habits, and physical activity will be collected through in-person interview using structured questionnaires. Blood samples (buccal cells when blood is not available) will be collected for DNA analysis. Associations between polymorphisms in the proposed genes and endometrial cancer risk and their interplay with lifestyle factors will be examined using unconditional logistic regression methods. Findings of this study will provide insights into the role of mitogenic growth factors and their interaction with lifestyle factors in the etiology of endometrial cancer.